Professional Education


  • Master of Science, Goteborgs Universitet (2010)
  • Doctor of Philosophy, Universitetet I Oslo (2019)

Stanford Advisors


All Publications


  • Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma BLOOD ADVANCES Koksal, H., Dillard, P., Josefsson, S. E., Maggadottir, S., Pollmann, S., Fane, A., Blaker, Y., Beiske, K., Huse, K., Kolstad, A., Holte, H., Kvalheim, G., Smeland, E. B., Myklebust, J. H., Inderberg, E., Walchli, S. 2019; 3 (8): 1230–43

    Abstract

    T cells modified to express chimeric antigen receptor (CAR) targeting CD19 (CD19CAR) have produced remarkable clinical responses in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. CD19CAR T-cell therapy has also demonstrated prominent effects in B-cell non-Hodgkin lymphoma (B-NHL) patients. However, a subset of patients who relapse after CD19CAR T-cell therapy have outgrowth of CD19- tumor cells. Hence, development of alternative CARs targeting other B-cell markers represents an unmet medical need for B-cell acute lymphoblastic leukemia and B-NHL. Here, we confirmed previous data by showing that, overall, B-NHL has high expression of CD37. A second-generation CD37CAR was designed, and its efficacy in T cells was compared with that of CD19CAR. In vitro assessment of cytotoxicity and T-cell function upon coculture of the CAR T cells with different target B-cell lymphoma cell lines demonstrated comparable efficacy between the 2 CARs. In an aggressive B-cell lymphoma xenograft model, CD37CAR T cells were as potent as CD19CAR T cells in controlling tumor growth. In a second xenograft model, using U2932 lymphoma cells containing a CD19- subpopulation, CD37CAR T cells efficiently controlled tumor growth and prolonged survival, whereas CD19CAR T cells had limited effect. We further show that, unlike CD19CAR, CD37CAR was not sensitive to antigen masking. Finally, CD37CAR reactivity was restricted to B-lineage cells. Collectively, our results demonstrated that CD37CAR T cells also can effectively eradicate B-cell lymphoma tumors when CD19 antigen expression is lost and support further clinical testing for patients with relapsed/refractory B-NHL.

    View details for DOI 10.1182/bloodadvances.2018029678

    View details for Web of Science ID 000465480800004

    View details for PubMedID 30979721

    View details for PubMedCentralID PMC6482360

  • TIGIT and PD-1 mark intratumoral T cells with reduced effector function in B-cell non-Hodgkin lymphoma. Cancer immunology research Josefsson, S. E., Beiske, K., Blaker, Y. N., Forsund, M. S., Holte, H., Ostenstad, B., Kimby, E., Koksal, H., Walchli, S., Bai, B., Smeland, E. B., Levy, R., Kolstad, A., Huse, K., Myklebust, J. H. 2019

    Abstract

    Checkpoint blockade can reverse T-cell exhaustion and promote antitumor responses. Although blocking the PD-1 pathway has been successful in Hodgkin lymphoma, response rates have been modest in B-cell non-Hodgkin lymphoma (NHL). Co-blockade of checkpoint receptors may therefore be necessary to optimize antitumor T-cell responses. Here, characterization of co-inhibitory receptor expression in intratumoral T cells from different NHL types identified TIGIT and PD-1 as frequently expressed co-inhibitory receptors. Tumors from NHL patients were enriched in CD8+ and CD4+ TEM cells that displayed high co-expression of TIGIT and PD-1, and co-expression of these checkpoint receptors identified T cells with reduced production of IFN-gamma, TNF-alpha and IL-2. The suppressed cytokine production could be improved upon in vitro culture in absence of ligands. Whereas PD-L1 was expressed by macrophages, the TIGIT ligands CD155 and CD112 were expressed by lymphoma cells in 39% and 50% of DLBCL cases and in some MCL cases, as well as by endothelium and FDCs in all NHLs investigated. Collectively, our results show that TIGIT and PD-1 mark dysfunctional T cells and suggest that TIGIT and PD-1 co-blockade should be further explored to elicit potent antitumor responses in patients with NHL.

    View details for DOI 10.1158/2326-6066.CIR-18-0351

    View details for PubMedID 30659053

  • T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling CLINICAL CANCER RESEARCH Josefsson, S. E., Huse, K., Kolstad, A., Beiske, K., Pende, D., Steen, C. B., Inderberg, E., Lingjaerde, O., Ostenstad, B., Smeland, E. B., Levy, R., Irish, J. M., Myklebust, J. H. 2018; 24 (4): 870–81

    Abstract

    Purpose: T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing coinhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets.Experimental Design: Surface expression of 9 coinhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of T-cell immunoglobulin and ITIM domain (TIGIT) ligands was detected by immunohistochemistry.Results: TIGIT was a frequently expressed coinhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly coexpressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFNγ, while TCR proximal signaling (p-CD3ζ, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored upon in vitro culture. The costimulatory receptor CD226 was downregulated in TIGIT+ compared with TIGIT- CD8 FL T cells, further skewing the balance toward immunosuppression.Conclusions: TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between coinhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients. Clin Cancer Res; 24(4); 870-81. ©2017 AACR.

    View details for DOI 10.1158/1078-0432.CCR-17-2337

    View details for Web of Science ID 000425191300015

    View details for PubMedID 29217528

    View details for PubMedCentralID PMC5815910